Difluoromethyl 2-Pyridyl Sulfone Research Articles

Sulfone Electrophiles in Cross-Electrophile Coupling: Nickel-Catalyzed Difluoromethylation of Aryl Bromides.

Fluoroalkyl fragments have played a critical role in the design of pharmaceutical and agrochemical molecules in recent years due to the enhanced biological properties of fluorinated molecules compared to their non-fluorinated analogues. Despite the potential advantages conferred by incorporating a difluoromethyl group in organic compounds, industrial adoption of difluoromethylation methods lags behind fluorination and trifluoromethylation. This is due in part to challenges in applying common difluoromethyl sources towards industrial applications. We report here the nickel-catalyzed cross-electrophile coupling of (hetero)aryl bromides with difluoromethyl 2-pyridyl sulfone, a sustainably sourced, crystalline difluoromethylation reagent. The scope of this reaction is demonstrated with 24 examples (67 ± 16% average yield) including a diverse array of heteroaryl bromides and precursors to difluoromethyl-containing preclinical pharmaceuticals. This reaction can be applied to small-scale parallel synthesis and benchtop scale-up under mild conditions. As sulfone reagents are uncommon electrophiles in cross-electrophile coupling, the mechanism of this process was investigated. Studies confirmed the formation of •CF2H instead of difluorocarbene. A series of modified difluoromethyl sulfones revealed that sulfone reactivity does not correlate exclusively with reduction potential and that coordination of cations or nickel to the pyridyl group is essential to reactivity, setting out parameters for matching the reactivity of sulfones in cross-electrophile coupling.

Switching from 2-pyridination to difluoromethylation: ligand-enabled nickel-catalyzed reductive difluoromethylation of aryl iodides with difluoromethyl 2-pyridyl sulfone

Switching from 2-pyridination to difluoromethylation: ligand-enabled nickel-catalyzed reductive difluoromethylation of aryl iodides with difluoromethyl 2-pyridyl sulfone

Nickel-Catalyzed Reductive 2-Pyridination of Aryl Iodides with Difluoromethyl 2-Pyridyl Sulfone

A novel nickel-catalyzed reductive cross-coupling between aryl iodides and difluoromethyl 2-pyridyl sulfone (2-PySO2CF2H) enables C(sp2)-C(sp2) bond formation through selective C(sp2)-S bond cleavage, which demonstrates the new reactivity of 2-PySO2CF2H reagent. This method employs readily available nickel catalyst and sulfones as cross-electrophile coupling partners, providing facile access to biaryls under mild reaction conditions without pregeneration of arylmetal reagents.

Iron-Catalyzed Difluoromethylation of Arylzincs with Difluoromethyl 2-Pyridyl Sulfone.

We report the first iron-catalyzed difluoromethylation of arylzincs with difluoromethyl 2-pyridyl sulfone via selective C-S bond cleavage. This method employs the readily available, bench-stable fluoroalkyl sulfone reagent and inexpensive iron catalyst, allowing facile access to structurally diverse difluoromethylated arenes at low temperatures. The experiment employing a radical clock indicates the involvement of radical species in this iron-catalyzed difluoromethylation process.

ChemInform Abstract: Nucleophilic Iododifluoromethylation of Carbonyl Compounds Using Difluoromethyl 2‐Pyridyl Sulfone.

A new, efficient method for iododifluoromethylation of carbonyl compounds utilizing difluoromethyl 2-pyridyl sulfone (2-PySO2CF2H) is described. This transformation is achieved by a nucleophilic addition of 2-PySO2CF2H with carbonyl compounds and a subsequent iodination of sulfinate, which is generated in situ by a novel zinc-mediated depyridination reaction. The method employs mild reaction conditions, exhibits excellent functional-group tolerance, and can be used in the synthesis of various iododifluoromethylated carbinols.

Nucleophilic Iododifluoromethylation of Carbonyl Compounds Using Difluoromethyl 2-Pyridyl Sulfone.

A new, efficient method for iododifluoromethylation of carbonyl compounds utilizing difluoromethyl 2-pyridyl sulfone (2-PySO2CF2H) is described. This transformation is achieved by a nucleophilic addition of 2-PySO2CF2H with carbonyl compounds and a subsequent iodination of sulfinate, which is generated in situ by a novel zinc-mediated depyridination reaction. The method employs mild reaction conditions, exhibits excellent functional-group tolerance, and can be used in the synthesis of various iododifluoromethylated carbinols.

Difluoromethyl 2-pyridyl sulfone: a versatile carbonyl gem-difluoroolefination reagent

The gem-difluoroolefination of carbonyl compounds with difluoromethyl 2-pyridyl sulfone (2-PySO2CF2H) has been summarized in this tutorial account.

Gem-Difluoroolefination of diaryl ketones and enolizable aldehydes with difluoromethyl 2-pyridyl sulfone: new insights into the Julia-Kocienski reaction.

The direct conversion of diaryl ketones and enolizable aliphatic aldehydes into gem-difluoroalkenes has been a long-standing challenge in organofluorine chemistry. Herein, we report efficient strategies to tackle this problem by using difluoromethyl 2-pyridyl sulfone as a general gem-difluoroolefination reagent. The gem-difluoroolefination of diaryl ketones proceeds by acid-promoted Smiles rearrangement of the carbinol intermediate; the gem-difluoroolefination is otherwise difficult to achieve through a conventional Julia-Kocienski olefination protocol under basic conditions due to the retro-aldol type decomposition of the key intermediate. Efficient gem-difluoroolefination of aliphatic aldehydes was achieved by the use of an amide base generated in situ (from CsF and tris(trimethylsilyl)amine), which diminishes the undesired enolization of aliphatic aldehydes and provides a powerful synthetic method for chemoselective gem-difluoroolefination of multi-carbonyl compounds. Our results provide new insights into the mechanistic understanding of the classical Julia-Kocienski reaction.

Synthesis of polymer electrolyte membranes based on poly(norbornene)s functionalized with pendant difluoroalkyl sulfonic acids

A novel difluoroalkanesulfonyl fluoride monomer, 2-(bicyclo[2.2.1]hept-5-en-2-yl)-1,1-difluoro-2- methoxypropane-1-sulfonyl fluoride, was synthesized in two steps. Nucleophilic addition of 2-acetyl-5-norbornene with difluoromethyl 2-pyridyl sulfone, followed by methylation with methyl trifluoromethanesulfonate produced substituted difluoromethyl 2-pyridyl sulfone. Removal of the pyridyl group with KOH/MeOH, and fluorination with Selectfluor afforded the desired monomer. Novel poly(norbornene)s containing pendent difluoroalkanesulfonic acids were synthesized by copolymerization of varying molar ratios of norbornene with difluoroalkanesulfonyl fluoride monomer by ring opening metathesis polymerization (ROMP) using Grubbs second-generation catalyst, followed by hydrolyzing under basic condition and treatment with aqueous HCl. Room temperature proton conductivity (12?49 mS/cm) was observed with these new type of membranes.

Difluoromethyl 2-Pyridyl Sulfone: A New gem-Difluoroolefination Reagent for Aldehydes and Ketones

Difluoromethyl 2-pyridyl sulfone, a previously unknown compound, was found to act as a novel and efficient gem-difluoroolefination reagent for both aldehydes and ketones. It was found that the fluorinated sulfinate intermediate in the reaction is relatively stable, which can be observed by (19)F NMR and trapped with CH(3)I.